RESUMO
MOTIVATION: Bioinformatic tools capable of annotating, rapidly and reproducibly, large, targeted lipidomic datasets are limited. Specifically, few programs enable high-throughput peak assessment of liquid chromatography-electrospray ionization tandem mass spectrometry data acquired in either selected or multiple reaction monitoring modes. RESULTS: We present here Bayesian Annotations for Targeted Lipidomics, a Gaussian naïve Bayes classifier for targeted lipidomics that annotates peak identities according to eight features related to retention time, intensity, and peak shape. Lipid identification is achieved by modeling distributions of these eight input features across biological conditions and maximizing the joint posterior probabilities of all peak identities at a given transition. When applied to sphingolipid and glycerophosphocholine selected reaction monitoring datasets, we demonstrate over 95% of all peaks are rapidly and correctly identified. AVAILABILITY AND IMPLEMENTATION: BATL software is freely accessible online at https://complimet.ca/batl/ and is compatible with Safari, Firefox, Chrome and Edge. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Lipidômica , Software , Teorema de Bayes , Espectrometria de Massas , Cromatografia Líquida/métodosRESUMO
Two recent, high-profile manuscripts reported negative results with two parallel approaches of passive immunization targeting α-synuclein in a population of patients with early Parkinson's disease (PD). These phase II studies failed to show a bona fide disease-modifying neuroprotective effect on PD progression, despite the evidence that these antibodies effectively bind native α-synuclein in human serum. Here, we discuss the possible reasons that could help explain the lack of clinical efficacy. In particular, we highlight (1) the wealth of evidence supporting the notion of α-synuclein as a valid therapeutic target; (2) the lack of evidence of target engagement in the aforementioned studies, especially of the elusive oligomeric species, the likely culprits in disease pathogenesis and/or its propagation; (3) the limitations, especially in terms of timing passive immunization, of preclinical models, where the same α-synuclein antibodies succeeded in mitigating disease manifestations; (4) the consideration of possibly intervening at an even earlier stage of disease in future trials; and (5) the multitude of strategies beyond passive immunization that could be used to combat α-synuclein-mediated neurodegeneration, if in the end the current approach is not fruitful. Overall, our perception is that converging developments in the field, among them novel bioassays and biomarkers, improved cellular and animal models and objective measurements of motor activities integrated into clinical trials, if further optimized, will gradually move the momentum of the field forward. This, to better test the concept of whether α-synuclein-targeting therapies can indeed deliver the "holy grail" of neuroprotection to the benefit of the PD community. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson , alfa-Sinucleína , Animais , Humanos , alfa-Sinucleína/antagonistas & inibidores , alfa-Sinucleína/imunologia , Anticorpos/imunologia , Anticorpos/uso terapêutico , Biomarcadores , Doença de Parkinson/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them. OBJECTIVE: This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for "defining the riddle" will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD. CONCLUSION: Accuracy in defining endophenotypes of "typical PD" across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Humanos , Doença de Parkinson/genética , Síndrome , Biomarcadores , Previsões , Sistema Nervoso Central/patologiaRESUMO
The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson's-linked neurodegeneration.
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Envelhecimento/metabolismo , Dopamina/metabolismo , Mesencéfalo/metabolismo , Degeneração Neural/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Animais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Mesencéfalo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Degeneração Neural/patologia , Oxirredução , Adulto JovemRESUMO
Parkinson's disease (PD) is one of the fastest-growing neurodegenerative disorders of increasing global prevalence. It represents the second most common movement disorder after tremor and the second most common neurodegenerative disorder after Alzheimer's disease. The incidence rate of idiopathic PD increases steadily with age, however, some variants of autosomal recessive inheritance are present with an early age-at-onset (ARPD). Approximately 50 percent of ARPD cases have been linked to bi-allelic mutations in genes encoding Parkin, DJ-1, and PINK1. Each protein has been implicated in maintaining proper mitochondrial function, which is particularly important for neuronal health. Aberrant post-translational modifications of these proteins may disrupt their cellular functions and thus contributing to the development of idiopathic PD. Some post-translational modifictions can be attributed to the dysregulation of potentially harmful reactive oxygen and nitrogen species inside the cell, which promote oxidative and nitrosative stress, respectively. Unlike oxidative modifications, the covalent modification by Nitric Oxide under nitrosative stress, leading to S-nitrosylation of Parkin, DJ-1; and PINK1, is less studied. Here, we review the available literature on S-nitrosylation of these three proteins, their implications in the pathogenesis of PD, and provide an overview of currently known, denitrosylating systems in eukaryotic cells.
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Óxido Nítrico/metabolismo , Estresse Nitrosativo , Doença de Parkinson/metabolismo , Proteína Desglicase DJ-1/metabolismo , Proteínas Quinases/metabolismo , Processamento de Proteína Pós-Traducional , Ubiquitina-Proteína Ligases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Humanos , Mutação , Óxido Nítrico/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , Proteína Desglicase DJ-1/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in both familial and sporadic Parkinson's disease (PD), yet its pathogenic role remains unclear. A previous screen in Drosophila identified Scar/WAVE (Wiskott-Aldrich syndrome protein-family verproline) proteins as potential genetic interactors of LRRK2 Here, we provide evidence that LRRK2 modulates the phagocytic response of myeloid cells via specific modulation of the actin-cytoskeletal regulator, WAVE2. We demonstrate that macrophages and microglia from LRRK2-G2019S PD patients and mice display a WAVE2-mediated increase in phagocytic response, respectively. Lrrk2 loss results in the opposite effect. LRRK2 binds and phosphorylates Wave2 at Thr470, stabilizing and preventing its proteasomal degradation. Finally, we show that Wave2 also mediates Lrrk2-G2019S-induced dopaminergic neuronal death in both macrophage-midbrain cocultures and in vivo. Taken together, a LRRK2-WAVE2 pathway, which modulates the phagocytic response in mice and human leukocytes, may define an important role for altered immune function in PD.
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Citofagocitose/fisiologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Células Mieloides/citologia , Doença de Parkinson/fisiopatologia , Família de Proteínas da Síndrome de Wiskott-Aldrich/metabolismo , Animais , Linhagem Celular , Drosophila , Humanos , Camundongos , Microglia , Células Mieloides/fisiologia , Transdução de Sinais/fisiologiaRESUMO
On May 26, 2020, Dr. Oleh Hornykiewicz died at the age of 93 years. His twin discoveries in the early 1960s of dopamine deficiency in the brains of subjects with Parkinson's disease and the amelioration of patients' symptoms by levodopa therapy represent milestone events in the history of medicine. These breakthroughs enabled much-needed relief for millions of patients suffering from neurological disorders every year and have given rise to the field of dopamine signaling in the regulation of complex behaviors in primates. What did Dr. Hornykiewicz, who was actively engaged in research until shortly before his 91st birthday, wish to pass on to younger scientists? What were his thoughts regarding the elusive cause of Parkinson's disease? How did he wish to be remembered? Here, the authors, one a former student and the other an admired colleague, recall messages conveyed by Dr. Hornykiewicz in public lectures; they also share the content of conversations and letters exchanged with him since 2004, as he began to reflect on his legacy. Through Dr. Hornykiewicz's own words and writings, the picture emerges of an extraordinarily committed scientist, who was exemplary in his professional integrity, who knew how to deploy a gallous sense of humor, who displayed little patience for physicians offering advice, and who kept any sense of pride over his monumental contributions private. When asked at the age of 91 years about the secrets of his long and fulfilled career in neuroscience, he identified himself as "a mad scientist. I am someone who continuously fantasizes. I am someone who chases fantastical ideas and who keeps on dreaming ", and as a man who was supported by the loving companionship of his wife, Christine. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Neurociências , Doença de Parkinson , Médicos , Dopamina , História do Século XX , Humanos , Levodopa , Masculino , Doença de Parkinson/tratamento farmacológicoRESUMO
PURPOSE: Integrated MD/PhD programs are relatively new in Canada and represent a platform to train the next generation of clinician-scientists. However, MD/PhD programs vary substantially by structure, funding and mentorship opportunities, and there exists a paucity of data on the overall students' successes and challenges. The purpose of this study is to assess objective and subjective metrics of the MD/PhD Program at the University of Ottawa. METHODS: Students in all years of the program were invited to complete a 58- question survey, and the resulting data were analyzed by descriptive statistics. RESULTS: Our survey had an 88.5% (23/26) participation rate. The program has been gaining interest and the number of applications increased by 178% between 2013 and 2018. Tuition support was considered an essential element in accepting the admission offer, as 47.8% of students would have declined admission without full tuition coverage. The MD/PhD students were heavily engaged in scholarly activities, with an average of 8.3 presentations/ publications per respondent. Respondents indicated low satisfaction with formal career planning advice (28.6% satisfied/very satisfied) and program transition guidance (22.2%). When delivered informally by peers, both career planning advice and program transition guidance were experienced as more satisfying (65.2% and 63.6%, respectively). Only 34.8% of survey respondents identified as female, highlighting the challenge of achieving diversity in clinician-scientist training programs. CONCLUSION: Our report contributes to the body of knowledge on concrete obstacles experienced by students within MD/PhD programs and key areas that can be improved upon-locally, provincially and nationally-to further advance student success.
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Pesquisa Biomédica , Médicos , Canadá , Criança , Feminino , Humanos , Mentores , Inquéritos e QuestionáriosRESUMO
Cerebrosides, including glucosylceramides (GlcCers) and galactosylceramides (GalCers), are important membrane components of animal cells with deficiencies resulting in devastating lysosomal storage disorders. Their quantification is essential for disease diagnosis and a better understanding of disease mechanisms. The simultaneous quantification of GlcCer and GalCer isomers is, however, particularly challenging due to their virtually identical structures. To address this challenge, we developed a new LC/MS-based method using differential ion mobility spectrometry (DMS) capable of rapidly and reproducibly separating and quantifying isomeric cerebrosides in a single run. We show that this LC/ESI/DMS/MS/MS method exhibits robust quantitative performance within an analyte concentration range of 2.8-355 nM. We further report the simultaneous quantification of nine GlcCers (16:0, 18:0, 20:0, 22:0, 23:0, 24:1, 24:0, 25:0, and 26:0) and five GalCers (16:0, 22:0, 23:0, 24:1, and 24:0) molecular species in human plasma, as well as six GalCers (18:0, 22:0, 23:0, 24:1, 24:0 and 25:0) and two GlcCers (24:1 and 24:0) in human cerebrospinal fluid. Our method expands the potential of DMS technology in the field of glycosphingolipid analysis for both biomarker discovery and drug screening by enabling the unambiguous assignment and quantification of cerebroside lipid species in biological samples.
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Cerebrosídeos/química , Cerebrosídeos/isolamento & purificação , Cromatografia Líquida/métodos , Espectrometria de Mobilidade Iônica/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Cerebrosídeos/sangue , Cerebrosídeos/líquido cefalorraquidiano , Cromatografia Líquida/normas , Feminino , Humanos , Espectrometria de Mobilidade Iônica/normas , Isomerismo , Pessoa de Meia-Idade , Padrões de Referência , Espectrometria de Massas por Ionização por Electrospray/normas , Espectrometria de Massas em Tandem/normas , Fatores de TempoRESUMO
Fifty-five years after the concept of dopamine replacement therapy was introduced, Parkinson disease (PD) remains an incurable neurological disorder. To date, no disease-modifying therapeutic has been approved. The inability to predict PD incidence risk in healthy adults is seen as a limitation in drug development, because by the time of clinical diagnosis ≥ 60% of dopamine neurons have been lost. We have designed an incidence prediction model founded on the concept that the pathogenesis of PD is similar to that of many disorders observed in ageing humans, i.e. a complex, multifactorial disease. Our model considers five factors to determine cumulative incidence rates for PD in healthy adults: (i) DNA variants that alter susceptibility (D), e.g. carrying a LRRK2 or GBA risk allele; (ii) Exposure history to select environmental factors including xenobiotics (E); (iii) Gene-environment interactions that initiate pathological tissue responses (I), e.g. a rise in ROS levels, misprocessing of amyloidogenic proteins (foremost, α-synuclein) and dysregulated inflammation; (iv) sex (or gender; G); and importantly, (v) time (T) encompassing ageing-related changes, latency of illness and propagation of disease. We propose that cumulative incidence rates for PD (PR ) can be calculated in healthy adults, using the formula: PR (%) = (E + D + I) × G × T. Here, we demonstrate six case scenarios leading to young-onset parkinsonism (n = 3) and late-onset PD (n = 3). Further development and validation of this prediction model and its scoring system promise to improve subject recruitment in future intervention trials. Such efforts will be aimed at disease prevention through targeted selection of healthy individuals with a higher prediction score for developing PD in the future and at disease modification in subjects that already manifest prodromal signs.
Assuntos
Interação Gene-Ambiente , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Dopamina/metabolismo , Humanos , Incidência , Mutação/genética , Doença de Parkinson/metabolismo , Proteínas Serina-Treonina Quinases/genética , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
BACKGROUND: Efforts to identify fluid biomarkers of Parkinson's disease (PD) have intensified in the last decade. As the role of inflammation in PD pathophysiology becomes increasingly recognized, investigators aim to define inflammatory signatures to help elucidate underlying mechanisms of disease pathogenesis and aid in identification of patients with inflammatory endophenotypes that could benefit from immunomodulatory interventions. However, discordant results in the literature and a lack of information regarding the stability of inflammatory factors over a 24-h period have hampered progress. METHODS: Here, we measured inflammatory proteins in serum and CSF of a small cohort of PD (n = 12) and age-matched healthy control (HC) subjects (n = 6) at 11 time points across 24 h to (1) identify potential diurnal variation, (2) reveal differences in PD vs HC, and (3) to correlate with CSF levels of amyloid ß (Aß) and α-synuclein in an effort to generate data-driven hypotheses regarding candidate biomarkers of PD. RESULTS: Despite significant variability in other factors, a repeated measures two-way analysis of variance by time and disease state for each analyte revealed that serum IFNγ, TNF, and neutrophil gelatinase-associated lipocalin (NGAL) were stable across 24 h and different between HC and PD. Regression analysis revealed that C-reactive protein (CRP) was the only factor with a strong linear relationship between CSF and serum. PD and HC subjects showed significantly different relationships between CSF Aß proteins and α-synuclein and specific inflammatory factors, and CSF IFNγ and serum IL-8 positively correlated with clinical measures of PD. Finally, linear discriminant analysis revealed that serum TNF and CSF α-synuclein discriminated between PD and HC with a minimum of 82% sensitivity and 83% specificity. CONCLUSIONS: Our findings identify a panel of inflammatory factors in serum and CSF that can be reliably measured, distinguish between PD and HC, and monitor inflammation as disease progresses or in response to interventional therapies. This panel may aid in generating hypotheses and feasible experimental designs towards identifying biomarkers of neurodegenerative disease by focusing on analytes that remain stable regardless of time of sample collection.
Assuntos
Mediadores da Inflamação/sangue , Mediadores da Inflamação/líquido cefalorraquidiano , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , alfa-Sinucleína/sangue , alfa-Sinucleína/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Doença de Parkinson/diagnóstico , Índice de Gravidade de DoençaRESUMO
Braak and Del Tredici have proposed that typical Parkinson disease (PD) has its origins in the olfactory bulb and gastrointestinal tract. However, the role of the olfactory system has insufficiently been explored in the pathogeneses of PD and Alzheimer disease (AD) in laboratory models. Here, we demonstrate applications of a new method to process mouse heads for microscopy by sectioning, mounting, and staining whole skulls ('holocranohistochemistry'). This technique permits the visualization of the olfactory system from the nasal cavity to mitral cells and dopamine-producing interneurons of glomeruli in the olfactory bulb. We applied this method to two specific goals: first, to visualize PD- and AD-linked gene expression in the olfactory system, where we detected abundant, endogenous α-synuclein and tau expression in the olfactory epithelium. Furthermore, we observed amyloid-ß plaques and proteinase-K-resistant α-synuclein species, respectively, in cranial nerve-I of APP- and human SNCA-over-expressing mice. The second application of the technique was to the modeling of gene-environment interactions in the nasal cavity of mice. We tracked the infection of a neurotropic respiratory-enteric-orphan virus from the nose pad into cranial nerves-I (and -V) and monitored the ensuing brain infection. Given its abundance in the olfactory epithelia, we questioned whether α-synuclein played a role in innate host defenses to modify the outcome of infections. Indeed, Snca-null mice were more likely to succumb to viral encephalitis versus their wild-type littermates. Moreover, using a bacterial sepsis model, Snca-null mice were less able to control infection after intravenous inoculation with Salmonella typhimurium. Together, holocranohistochemistry enabled new discoveries related to α-synuclein expression and its function in mice. Future studies will address: the role of Mapt and mutant SNCA alleles in infection paradigms; the contribution of xenobiotics in the initiation of idiopathic PD; and the safety to the host when systemically targeting α-synuclein by immunotherapy.
Assuntos
Encéfalo/metabolismo , Encéfalo/virologia , Encefalite Viral/virologia , Mucosa Olfatória/anatomia & histologia , Mucosa Olfatória/metabolismo , Infecções por Reoviridae/virologia , alfa-Sinucleína/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Modelos Animais de Doenças , Encefalite Viral/imunologia , Encefalite Viral/mortalidade , Encefalite Viral/patologia , Feminino , Cabeça , Humanos , Imuno-Histoquímica , Masculino , Orthoreovirus Mamífero 3 , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/anatomia & histologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Vias Neurais/patologia , Mucosa Olfatória/patologia , Neurônios Receptores Olfatórios/metabolismo , Neurônios Receptores Olfatórios/virologia , Infecções por Reoviridae/imunologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/patologia , Salmonella typhimurium , Preservação de Tecido/métodos , alfa-Sinucleína/genéticaRESUMO
Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. In Alzheimer's disease, levels of increased CSF tau protein and decreased levels of ß-amyloid 1-42 (Aß42) have been shown to correlate with brain plaque formation and tangle pathology. Intracellular Lewy inclusions containing aggregated α-synuclein (α-syn) represent a pathological hallmark of Parkinson's disease (PD). In most - but not all - studies published to date total CSF α-syn concentrations have been found to be decreased in disorders related to α-syn pathology, that is, PD, dementia with Lewy bodies and multiple system atrophy. However, these reports show extensive signal overlap among tested individuals, thereby diminishing its potential for routine use in clinical practice. To investigate potential biological (i.e., non-technical) confounders of reported CSF levels for α-syn, Aß42, and tau in PD and related disorders, we carried out a methodical review of known factors that underlie signal variability and speculate on those that have not yet been tested. We discuss several biological factors, such as neuropathology, demographics, clinical phenotype, progression and duration of disease, concomitant illnesses and, last but not least, pharmacotherapy, which in isolation or combination can substantially alter values for CSF proteins of interest. Enhanced implementation of standardized clinical protocols, streamlined operating procedures, and further progress in the development of validated assays for CSF proteins have the potential to (i) inform us as to the pathogenesis of disease, (ii) support the laboratory-based diagnosis for symptomatic subjects in the future, and (iii) facilitate breakthrough therapies to alter the course of neurodegenerative disorders, such as PD and Alzheimer's disease. Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. To investigate potential biological confounders of reported CSF levels for α-synuclein (α-Syn), amyloid-ß 1-42(Aß42) and tau protein in Parkinson's disease and related disorders, we reviewed the current literature for known factors that underlie signal variability and speculate on those that have not yet been tested. This article is part of a special issue on Parkinson disease.
Assuntos
Proteínas do Líquido Cefalorraquidiano/líquido cefalorraquidiano , Transtornos Cognitivos/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Biomarcadores/líquido cefalorraquidiano , Ensaios Clínicos como Assunto/métodos , Transtornos Cognitivos/diagnóstico , Humanos , Doença de Parkinson/diagnóstico , Fragmentos de Peptídeos/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.
Assuntos
Doença de Parkinson/genética , Doença de Parkinson/patologia , alfa-Sinucleína/sangue , alfa-Sinucleína/genética , Idoso , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Regulação da Expressão Gênica , Testes Genéticos , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Neuroimagem , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , RNA Mensageiro/metabolismo , Cintilografia , Índice de Gravidade de Doença , TropanosRESUMO
Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results suggest that combining several CSF fluid biomarkers may be more successful than using single markers, at least for the diagnosis. Currently, the clinically most useful markers may comprise a combination of the light chain of neurofilament (which is consistently elevated in MSA compared to controls and Parkinson's disease), metabolites of the catecholamine pathway and proteins such as α-synuclein, DJ-1 and total-tau. Beyond future efforts in biomarker discovery, the harmonization of standard operating procedures will be crucial for future success.
Assuntos
Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Atrofia de Múltiplos Sistemas/diagnóstico , Animais , Encéfalo/metabolismo , Catecolaminas/análise , Humanos , Filamentos Intermediários/metabolismo , Atrofia de Múltiplos Sistemas/sangue , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Degeneração Neural/metabolismo , alfa-Sinucleína/análiseRESUMO
DJ-1 mutations cause autosomal recessive early-onset Parkinson disease (PD). We report a model of PD pathology: the DJ1-C57 mouse. A subset of DJ-1-nullizygous mice, when fully backcrossed to a C57BL/6 [corrected] background, display dramatic early-onset unilateral loss of dopaminergic (DA) neurons in their substantia nigra pars compacta, progressing to bilateral degeneration of the nigrostriatal axis with aging. In addition, these mice exhibit age-dependent bilateral degeneration at the locus ceruleus nucleus and display mild motor behavior deficits at aged time points. These findings effectively recapitulate the early stages of PD. Therefore, the DJ1-C57 mouse provides a tool to study the preclinical aspects of neurodegeneration. Importantly, by exome sequencing, we identify candidate modifying genes that segregate with the phenotype, providing potentially critical clues into how certain genes may influence the penetrance of DJ-1-related degeneration in mice.
Assuntos
Neurônios Dopaminérgicos/patologia , Peptídeos e Proteínas de Sinalização Intracelular , Locus Cerúleo/patologia , Proteínas do Tecido Nervoso , Proteínas Oncogênicas , Doença de Parkinson/genética , Doença de Parkinson/patologia , Substância Negra/patologia , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Humanos , Locus Cerúleo/metabolismo , Camundongos , Camundongos Knockout , Doença de Parkinson/metabolismo , Substância Negra/metabolismoRESUMO
Parkinson's disease is characterized by the pathological aggregation of Alpha-synuclein. The dual-hit hypothesis proposed by Braak implicates the enteric nervous system as an initial site of α-synuclein aggregation with subsequent spread to the central nervous system. Regional variations in the spatial pattern or levels of α-synuclein along the enteric nervous system could have implications for identifying sites of onset of this pathogenic cascade. We performed immunohistochemical staining for α-synuclein on gastrointestinal tissue from patients with no history of neurological disease using the established LB509 antibody and a new clone, MJFR1, characterized for immunohistochemistry here. We demonstrate that the vermiform appendix is particularly enriched in α-synuclein-containing axonal varicosities, concentrated in its mucosal plexus rather than the classical submucosal and myenteric plexuses. Unexpectedly, intralysosomal accumulations of α-synuclein were detected within mucosal macrophages of the appendix. The abundance and accumulation of α-synuclein in the vermiform appendix implicate it as a candidate anatomical locus for the initiation of enteric α-synuclein aggregation and permits the generation of testable hypotheses for Parkinson's disease pathogenesis.
Assuntos
Mucosa Gástrica/metabolismo , Trato Gastrointestinal/metabolismo , alfa-Sinucleína/análise , alfa-Sinucleína/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Humanos , Macrófagos/metabolismo , Pessoa de Meia-Idade , Fibras Nervosas/metabolismo , Sinaptofisina/metabolismo , Ubiquitina Tiolesterase/metabolismo , Peptídeo Intestinal Vasoativo/metabolismoRESUMO
Emerging genetic and clinical evidence suggests a link between Gaucher disease and the synucleinopathies Parkinson disease and dementia with Lewy bodies. Here, we provide evidence that a mouse model of Gaucher disease (Gba1(D409V/D409V)) exhibits characteristics of synucleinopathies, including progressive accumulation of proteinase K-resistant α-synuclein/ubiquitin aggregates in hippocampal neurons and a coincident memory deficit. Analysis of homozygous (Gba1(D409V/D409V)) and heterozygous (Gba1(D409V/+) and Gba1(+/-)) Gaucher mice indicated that these pathologies are a result of the combination of a loss of glucocerebrosidase activity and a toxic gain-of-function resulting from expression of the mutant enzyme. Importantly, adeno-associated virus-mediated expression of exogenous glucocerebrosidase injected into the hippocampus of Gba1(D409V/D409V) mice ameliorated both the histopathological and memory aberrations. The data support the contention that mutations in GBA1 can cause Parkinson disease-like α-synuclein pathology, and that rescuing brain glucocerebrosidase activity might represent a therapeutic strategy for GBA1-associated synucleinopathies.